Usage
- Dapagliflozin + Linagliptin + Metformin is prescribed for the management of type 2 diabetes mellitus in adults, specifically to improve glycemic control when metformin monotherapy is insufficient. It is also used to lower the risk of cardiovascular death in patients with type 2 diabetes and established cardiovascular disease.
- Pharmacological Classification: Antidiabetic combination therapy, comprising a sodium-glucose co-transporter 2 (SGLT2) inhibitor (dapagliflozin), a dipeptidyl peptidase-4 (DPP-4) inhibitor (linagliptin), and a biguanide (metformin).
- Mechanism of Action: This combination works synergistically through multiple mechanisms to lower blood glucose:
- Dapagliflozin increases urinary glucose excretion by inhibiting SGLT2 in the kidneys.
- Linagliptin increases incretin levels (GLP-1 and GIP), which stimulate insulin release and decrease glucagon secretion.
- Metformin decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity.
Alternate Names
- There are no widely recognized alternate names for this specific three-drug combination. The individual components may be known by other names (e.g., dapagliflozin is sometimes referred to as BMS-512148).
- Brand Names: This combination is available under various brand names depending on the region, such as Trijardy XR (when it contains empagliflozin instead of dapagliflozin).
How It Works
- Pharmacodynamics: The combined effect of the three drugs results in a significant reduction in HbA1c, fasting plasma glucose, and postprandial glucose. Dapagliflozin promotes weight loss through caloric loss in the urine, while linagliptin and metformin are generally weight-neutral or may promote modest weight loss.
- Pharmacokinetics:
- Dapagliflozin: Orally administered, rapidly absorbed, peak plasma concentration in 2 hours. Primarily eliminated through renal excretion (75%) and metabolism (21%), with a half-life of approximately 12 hours.
- Linagliptin: Orally administered, rapidly absorbed, peak plasma concentration in 1-4 hours. Primarily eliminated through biliary/fecal excretion (85%), with a half-life of approximately 12 days.
- Metformin: Orally administered, gradually absorbed. Not metabolized and is excreted unchanged in the urine, with a half-life of approximately 6 hours.
- Mode of Action:
- Dapagliflozin: Inhibits SGLT2 in the renal proximal tubules, blocking glucose reabsorption.
- Linagliptin: Reversibly inhibits DPP-4, the enzyme responsible for degrading incretins.
- Metformin: Activates AMP-activated protein kinase (AMPK), leading to multiple downstream effects on glucose metabolism.
- Receptor Binding/Enzyme Inhibition: Dapagliflozin selectively binds to and inhibits SGLT2. Linagliptin selectively inhibits DPP-4. Metformin does not bind to any known receptors.
- Elimination Pathways:
- Dapagliflozin: Renal and hepatic.
- Linagliptin: Biliary/fecal.
- Metformin: Renal.
Dosage
Standard Dosage
This fixed-dose combination comes in various formulations with different strengths and may need to be adjusted accordingly.
Children: This combination is not recommended for pediatric patients.
Special Cases:
- Elderly Patients: Dose adjustment may be required based on renal function.
- Patients with Renal Impairment: Contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) or end-stage renal disease. Dose adjustment required for moderate impairment.
- Patients with Hepatic Dysfunction: Contraindicated in patients with hepatic impairment.
- Patients with Comorbid Conditions: Caution should be exercised in patients with heart failure, urinary tract infections, dehydration, or volume depletion.
Clinical Use Cases
This specific drug combination does not have specific dosages for acute clinical situations like intubation, surgical procedures, mechanical ventilation, or ICU use. Diabetic management in these situations requires individualized assessment and may involve insulin therapy.
Dosage Adjustments
Dose adjustments are primarily based on renal function and individual patient response.
Side Effects
Common Side Effects:
- Genital fungal infections
- Urinary tract infections
- Nasopharyngitis
- Diarrhea
- Nausea
- Increased urination
Rare but Serious Side Effects:
- Hypersensitivity reactions (angioedema, anaphylaxis)
- Pancreatitis
- Ketoacidosis
- Severe and disabling arthralgia
- Hypotension
- Acute kidney injury
- Fournier’s gangrene (rare)
- Bullous pemphigoid
Long-Term Effects:
- Potential long-term effects are primarily related to chronic complications of diabetes and underlying cardiovascular disease.
Adverse Drug Reactions (ADR): Clinically significant ADRs require prompt discontinuation of the medication and supportive care. These include hypersensitivity reactions, acute pancreatitis, and ketoacidosis.
Contraindications
- Severe renal impairment or end-stage renal disease.
- Dialysis.
- Hypersensitivity to any component of the medication.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
- Severe hepatic impairment.
Drug Interactions
- Diuretics (thiazides, loop diuretics): Increased risk of hypotension and dehydration.
- Insulin or insulin secretagogues: Increased risk of hypoglycemia.
- CYP3A4 inducers (rifampin, phenytoin): May decrease dapagliflozin concentrations.
- Cationic drugs eliminated by renal tubular secretion (cimetidine): May increase metformin concentrations.
- Alcohol: Increased risk of lactic acidosis with metformin.
- Iodinated contrast media: Increased risk of acute kidney injury.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Category C (consult a healthcare professional). Dapagliflozin is not recommended during pregnancy, especially the second and third trimesters. Linagliptin’s safety in pregnancy has not been established. Metformin is generally considered safe in pregnancy, but insulin is preferred.
- Breastfeeding: The drug is not recommended during breastfeeding as it is unknown whether components are excreted in human milk.
Drug Profile Summary
- Mechanism of Action: Multifaceted, targeting renal glucose reabsorption, incretin activity, and hepatic glucose production.
- Side Effects: Genital/urinary infections, nasopharyngitis, diarrhea, nausea, hypoglycemia (with concurrent secretagogues), hypersensitivity reactions, pancreatitis (rare).
- Contraindications: Severe renal/hepatic impairment, dialysis, metabolic acidosis, hypersensitivity.
- Drug Interactions: Diuretics, insulin/secretagogues, CYP3A4 inducers, cationic drugs.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Individualized based on patient’s regimen and renal function.
- Monitoring Parameters: HbA1c, fasting and postprandial glucose, renal function (eGFR), weight, blood pressure, signs of infections.
Popular Combinations
This combination itself incorporates three common antidiabetic agents. It is sometimes combined with other agents like insulin or GLP-1 receptor agonists when further glycemic control is needed.
Precautions
- Monitor renal function, particularly in elderly patients and those with renal impairment.
- Monitor for signs of urinary and genital infections.
- Encourage adequate hydration, especially in hot weather or during strenuous activity.
- Advise patients on dietary restrictions and lifestyle modifications.
- Cautious use in patients with a history of pancreatitis.
FAQs (Frequently Asked Questions)
A: The starting dose varies based on the current regimen but often begins with dapagliflozin 10mg, linagliptin 5mg, and metformin 1000mg taken once daily. The dosage can be adjusted based on individual patient needs and tolerability, up to a maximum of dapagliflozin 10mg, linagliptin 5mg, and metformin 2000mg daily.
Q2: What are the major contraindications for this combination?
A: Severe renal or hepatic impairment, end-stage renal disease, patients on dialysis, hypersensitivity to any component, and acute or chronic metabolic acidosis.
Q3: Can this combination be used in patients with type 1 diabetes?
A: No. This combination is specifically indicated for type 2 diabetes.
Q4: How does this combination compare to other diabetes medications?
A: It offers a synergistic approach by targeting multiple glucose regulatory pathways. Compared to other combinations or monotherapies, it can achieve greater HbA1c reduction. The choice of medication depends on individual patient characteristics.
Q5: What are the most common side effects?
A: Genital mycotic infections, urinary tract infections, increased urination, nasopharyngitis, and gastrointestinal upset (diarrhea, nausea).
Q6: Are there any specific dietary or lifestyle recommendations while taking this medication?
A: Patients should follow a healthy diet low in refined carbohydrates and engage in regular physical activity. Adequate hydration is crucial, especially due to the diuretic effect of dapagliflozin.
Q7: How should this medication be taken?
A: Orally, once daily with a meal. The tablets should be swallowed whole and not crushed or chewed.
Q8: What are the monitoring parameters for this medication?
A: HbA1c, fasting and postprandial plasma glucose, renal function (eGFR), electrolytes, weight, blood pressure, and clinical signs of infection (genital, urinary).
Q9: Can I take this drug while pregnant or breastfeeding?
A: The combination is generally not recommended during pregnancy or breastfeeding. Alternative diabetes management strategies should be discussed with your doctor.
Q10: How should this drug be stored?
A: Store in a cool, dry place away from moisture and direct sunlight. It is usually recommended to store it at room temperature (25°C).
